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    Summary
    EudraCT Number:2014-004944-37
    Sponsor's Protocol Code Number:MK3475-054-04
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2015-04-21
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedGermany - PEI
    A.2EudraCT number2014-004944-37
    A.3Full title of the trial
    Adjuvant immunotherapy with anti-PD-1 monoclonal antibody Pembrolizumab (MK-3475) versus placebo after complete resection of high-risk Stage III melanoma: A randomized, double-blind Phase 3 trial of the EORTC Melanoma Group.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Immunotherapeutic treatment with Pembrolizumab (antibody) in melanoma patients at high risk of recurrence after complete surgical resection
    A.3.2Name or abbreviated title of the trial where available
    Immunotherapy with anti-PD in stage III melanoma
    A.4.1Sponsor's protocol code numberMK3475-054-04
    A.5.4Other Identifiers
    Name:EORTCNumber:1325-MG
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorMerck Sharp & Dohme Corp., a Subsidiary of Merck & Co. Inc
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportMerck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMerck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc
    B.5.2Functional name of contact pointGlobal Clinical Trials Operations
    B.5.3 Address:
    B.5.3.1Street Address351 Sumneytown Pike, UG4D-072
    B.5.3.2Town/ cityNorth Wales
    B.5.3.3Post codePA 19454
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1 267-305-4563
    B.5.5Fax number+1 267-235-6413
    B.5.6E-mailnageatte.ibrahim@merck.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product namePembrolizumab
    D.3.2Product code MK-3475
    D.3.4Pharmaceutical form Powder for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNPEMBROLIZUMAB
    D.3.9.1CAS number 1374853-91-4
    D.3.9.2Current sponsor codeMK-3475
    D.3.9.3Other descriptive nameAnti-PD-1 monoclonal antibody
    D.3.9.4EV Substance CodeSUB167136
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) Yes
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Keytruda®
    D.2.1.1.2Name of the Marketing Authorisation holderMerck Sharp & Dohme B.V.
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product namePembrolizumab
    D.3.2Product code MK-3475
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNPEMBROLIZUMAB
    D.3.9.1CAS number 1374853-91-4
    D.3.9.2Current sponsor codeMK-3475
    D.3.9.3Other descriptive nameAnti-PD-1 monoclonal antibody
    D.3.9.4EV Substance CodeSUB167136
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) Yes
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Stage III melanoma (AJCC R0) with histologically confirmed cutaneous melanoma metastatic to lymph node, classified as (AJCC, 2010): Stage IIIA with metastasis > 1 mm; any Stage IIIB or IIIC (no in-transit metastases)
    E.1.1.1Medical condition in easily understood language
    Clinical and histologic stage III melanoma with a high risk of recurrence
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10025670
    E.1.2Term Malignant melanoma stage III
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    - To prospectively assess whether post-operative adjuvant therapy with pembrolizumab improves recurrence-free survival, as compared to placebo in high-risk patients with complete resection of Stage IIIA (>1 mm metastasis), IIIB and IIIC melanoma.
    - To prospectively assess whether in the subgroup of patients with PD-L1-positive tumor expression, pembrolizumab improves recurrence-free survival as compared to placebo.
    E.2.2Secondary objectives of the trial
    - To prospectively assess whether post-operative adjuvant therapy with pembrolizumab improves distant metastasis free survival as compared to placebo.
    - To prospectively assess whether in the subgroup of patients with PD-L1-positive tumor expression pembrolizumab improves distant metastasis free survival as compared to placebo.
    - To prospectively assess whether post-operative adjuvant therapy with pembrolizumab improves overall survival, as compared to placebo.
    - To prospectively assess whether in the subgroup of patients with PD-L1-positive tumor expression pembrolizumab improves overall survival as compared to placebo.
    - To compare adverse event profiles (AE and Serious Adverse Event (SAE)) between patients receiving pembrolizumab versus patients in the placebo arm.
    - To evaluate the pharmacokinetics (PK) of pembrolizumab when pembrolizumab is administered at 200 mg every three weeks.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - At least 18 years of age.
    - Complete resection of Stage III melanoma (AJCC R0) with histologically confirmed cutaneous melanoma metastatic to lymph node, classified as (AJCC, 2010): Stage IIIA with metastasis > 1 mm; any Stage IIIB or IIIC. No past or current in-transit metastases or satellitosis.
    - Melanoma with unknown origin of the primary is eligible
    - Mandatory to ship tumor sample for evaluation of PD-L1 expression.
    - The treatment should start no later than 13 weeks after surgery and only after complete wound healing from the surgery.
    Note: if there is a delay of 1-7 days exceeding 13 weeks due to extreme unforeseen circumstances, the eligibility should be discussed with the medical monitor.
    - Disease status for the post-surgery baseline assessment must be documented by full Chest/Abdomen/Pelvis CT and/or MRI with Neck CT and/or MRI (for Head and Neck primaries) and complete clinical examination after the informed consent and prior to enrollment.
    Note: if a patient had laboratory/imaging tests as part of local routine guidelines (standard of care) prior to signing informed consent, the procedures will be acceptable for screening purposes if they are within the window required by the protocol.
    - Disease-free (no loco-regional relapse or distant metastasis); no clinical evidence for brain metastases.
    - BRAF mutation status (known or not done).
    - ECOG performance status of 0 or 1.
    - Patient demonstrates adequate organ function as defined in the protocol
    - Women of child bearing potential (WOCBP) must have a negative serum (or urine) pregnancy test within 72 hours prior to the first dose of study treatment.
    - Patients of childbearing / reproductive potential should use adequate birth control methods.
    - Female patients who are breast feeding should discontinue nursing prior to the first dose of study treatment and until 120 days after the last dose of study drug.

    Please refer to the Diagnosis and Main Criteria for Inclusion in the Protocol for the full list of inclusion criteria.
    E.4Principal exclusion criteria
    - Mucosal or ocular melanoma.
    - Prior therapy for melanoma except surgery for primary melanoma lesions.
    - history of (non-infectious) pneumonitis that required steroids or current pneumonitis. History of or current interstitial lung disease.
    - history of a hematologic or primary solid tumor malignancy, unless no evidence of that disease for 5 years.
    - active autoimmune disease that has required systemic treatment in past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic
    treatment.
    - active infection requiring therapy.
    - diagnosis of immunodeficiency, no systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment
    - known history of human immunodeficiency virus (HIV), active Hepatitis B or Hepatitis C.
    - treatment with live vaccines within 30 days prior to the first dose of study medication are not eligible.
    - prior treatment with any anti-CTLA4 monoclonal antibody or anti-PD-1, or PD-L1 or PD-L2 agent.
    - Patient is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigation device within 4 weeks prior to the first dose of treatment
    - patient is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling or child) who is investigational site or Sponsor staff directly involved with this trial, unless prospective IRB
    approval (by chair or designee) is given allowing exception to this criterion for a specific subject.
    - female patients who are Breast feeding
    E.5 End points
    E.5.1Primary end point(s)
    1. Recurrence free survival (RFS)
    2. RFS in subgroup of patients with PD-L1-positive tumor expression receiving either pembrolizumab or placebo
    E.5.1.1Timepoint(s) of evaluation of this end point
    1. Every 12 weeks during treatment and for the first two years. From year 3 to 5, every 6 months and yearly thereafter.
    2. Every 12 weeks during treatment and for the first two years. From year 3 to 5, every 6 months and yearly thereafter
    E.5.2Secondary end point(s)
    1. Distant metastases-free survival (DMFS)
    2. DMFS in subgroup of patients with PD-L1-positive tumor expression receiving either pembrolizumab or placebo
    3. Overall survival (OS)
    4. OS in subgroup of patients with PD-L1-positive tumor expression receiving either pembrolizumab or placebo
    5. Toxicity profile according to Common Terminology Criteria for Adverse Events (CTCAE) v. 4.0
    6. To evaluate the pharmacokinetics (PK) of pembrolizumab when pembrolizumab is administered 200 mg every 3 weeks
    7. To assess for development of anti-drug antibodies (ADA)
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. Every 12 weeks during treatment and for the first two years. From year 3 to 5, every 6 months and yearly thereafter.
    2. Every 12 weeks during treatment and for the first two years. From year 3 to 5, every 6 months and yearly thereafter.
    3. OS will be measured from the date of randomization until the date of death.
    4. OS will be measured from the date of randomization until the date of death.
    5. Every 6 weeks during treatment and at 12 weeks after the last treatment
    6. prior to traetment start (before injection 1), week 4 (before injection N°2), week 10 (before injection N°4 ), week 22 (before injection N°8 ) and at 12 months (before injection 16). At 30 days after the last treatment
    7. Prior to treatment start, weeks 4, 10, 22 and at 12 months. At 30 days after the last treatment
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety No
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group No
    E.8.1.6Cross over Yes
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned16
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA89
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    Austria
    Belgium
    Canada
    Czechia
    Denmark
    Finland
    France
    Germany
    Israel
    Italy
    Japan
    Korea, Republic of
    Netherlands
    New Zealand
    Norway
    Poland
    Portugal
    Russian Federation
    Serbia
    Singapore
    Slovenia
    Spain
    Sweden
    Switzerland
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    When all criteria have been satisfied:
    1. 30 days after all patients have stopped protocol treatment
    2. The trial is mature for the 3 final analyses of the efficacy endpoints: one for RFS (overall, and in PD-L1-positive), one for DMFS (overall, and in PD-L1-positive) and one for OS (overall, and in PD-L1-positive)
    3. The database has been fully cleaned and frozen
    4. As in other EORTC melanoma adjuvant trials, a very long term follow-up, when all patients have a 10-year follow-up is foreseen
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years8
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years8
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 738
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 162
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state278
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 540
    F.4.2.2In the whole clinical trial 900
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    None
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2015-07-22
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-08-27
    P. End of Trial
    P.End of Trial StatusOngoing
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